{"gene":"ULK3","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2015,"finding":"ULK3 phosphorylates ESCRT-III subunits (including IST1 and CHMP4C) via tandem MIT domains, delaying cytokinetic abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Structural and biochemical studies revealed an unusually tight interaction between ULK3 and IST1. IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint, and ULK3 and CHMP4C are functionally linked components of the abscission timer.","method":"Structural studies, in vitro phosphorylation assays, Co-IP/binding assays, mutagenesis, cell biological assays with lagging chromosome readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural, biochemical reconstitution, mutagenesis, and cellular epistasis all in one rigorous study","pmids":["26011858"],"is_preprint":false},{"year":2009,"finding":"ULK3 is an autophosphorylated serine/threonine kinase that phosphorylates GLI1 and GLI2 transcription factors in vitro, enhances their transcriptional activity, and alters subcellular localization of GLI1. Catalytic activity of ULK3 is required for its positive regulatory function in the SHH pathway.","method":"In vitro kinase assay, GLI-luciferase reporter assay, immunofluorescence, immunoblotting, kinase-dead mutant analysis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus reporter assays and localization, single lab with multiple orthogonal methods","pmids":["19878745"],"is_preprint":false},{"year":2010,"finding":"ULK3 interacts with Suppressor of Fused (Sufu) through its kinase domain. Sufu blocks ULK3 autophosphorylation and abolishes ULK3-mediated phosphorylation and positive regulation of GLI proteins. SHH signaling destabilizes the Sufu-ULK3 complex and releases ULK3. The Sufu-ULK3 complex co-expressed with GLI2 promotes generation of the GLI2 repressor form, establishing a dual (kinase-dependent and kinase-independent) function for ULK3 in SHH signaling.","method":"Co-immunoprecipitation, in vitro kinase assay, GLI-luciferase reporter assay, siRNA knockdown, immunoblotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional follow-up, in vitro kinase assay, single lab with multiple methods","pmids":["20643644"],"is_preprint":false},{"year":2017,"finding":"Decreased CSL upregulates ULK3 expression in human dermal fibroblasts. ULK3 binds and activates GLI2, thereby contributing to conversion of fibroblasts into cancer-associated fibroblasts (CAFs). ULK3 also independently induces autophagy in this context (unlinked from GLI/CAF activation). ULK3 silencing suppresses the tumor-enhancing properties of CAFs.","method":"Co-immunoprecipitation (ULK3-GLI2 binding), siRNA knockdown, autophagy assays, CAF functional assays, tumor co-injection models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for binding, KD with defined CAF/autophagy phenotype, single lab with multiple orthogonal methods","pmids":["28877478"],"is_preprint":false},{"year":2021,"finding":"ULK3-dependent activation of GLI1 contributes to transcriptional upregulation of DNMT3A upon autophagy induction, linking ULK3 kinase activity in the SHH pathway to epigenetic regulation of autophagy-related gene expression. Proximity ligation assay confirmed ULK3-GLI1 interaction in this context.","method":"Proximity ligation assay (PLA), chromatin immunoprecipitation (ChIP), RT-qPCR, siRNA knockdown, autophagy induction assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — PLA for interaction, ChIP for transcriptional regulation, siRNA KD, single lab with multiple methods","pmids":["35226587"],"is_preprint":false},{"year":2023,"finding":"ULK3 localizes to the nucleus in keratinocytes and SCC cells, where it directly binds and regulates the activity of histone arginine methyltransferases PRMT1 and PRMT5. ULK3 loss compromises PRMT1/5 chromatin association at specific genes and reduces overall methylation of histone H4. ULK3 silencing reduces proliferation, clonogenicity, and tumorigenic potential of SCC cells.","method":"Co-IP (ULK3-PRMT1/5 binding), chromatin fractionation, histone methylation assays, gene silencing (siRNA, LNA), nuclear localization imaging, orthotopic cancer models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, chromatin assays, histone methylation readout, functional KD in multiple SCC models, single lab with multiple orthogonal methods","pmids":["36797248"],"is_preprint":false},{"year":2016,"finding":"The Drosophila ULK3 ortholog ADUK induces autophagy independently of Atg1. ADUK interacts with Atg1 complex members Atg13 and FIP200 (200 kDa FAK family kinase-interacting protein), and requires Atg13 but not Atg1 for autophagy induction. Loss of ADUK shortens adult lifespan and reduces the autophagic response to chemical stress.","method":"Co-immunoprecipitation (ADUK-Atg13/FIP200), genetic loss-of-function (ADUK mutant flies), autophagy flux assays, lifespan analysis","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic LOF in Drosophila ortholog, single lab with multiple methods","pmids":["27717182"],"is_preprint":false},{"year":2018,"finding":"Autophosphorylation of ULK3 has no impact on its kinase activity. Phosphorylation of two specific residues in the ULK3 kinase domain by an unidentified kinase completely abolishes catalytic activity. The small molecule SU6668 binds in the ATP pocket of ULK3 yet inhibits ULK3 in a partially ATP non-competitive manner. The annotated kinase domain alone is insufficient for ULK3 kinase activity; additional amino acids in the 271–300 region are required.","method":"In vitro kinase assay, phosphorylation site mapping (mass spectrometry), site-directed mutagenesis, inhibitor binding studies (competitive kinetics)","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and inhibitor kinetics, single lab with multiple biochemical methods","pmids":["30096229"],"is_preprint":false},{"year":2021,"finding":"High-resolution crystal structures of the ULK3 kinase domain were determined, revealing unique structural features compared to other ULK kinases. A conformational switch between active and inactive ULK3 conformations was identified, controlled by the properties of attached small-molecule binders. A potential substrate-recognition mechanism of full-length ULK3 was described based on structural analysis.","method":"X-ray crystallography of ULK3 kinase domain, inhibitor co-crystallization, inhibitor fingerprinting panel","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structures with multiple inhibitor complexes and conformational analysis, single lab but structurally rigorous","pmids":["34190988"],"is_preprint":false},{"year":2024,"finding":"ULK3 expression is MTOR-insensitive and supports autophagosome formation in BIN1-deficient hippocampal neurons. Reducing ULK3 activity with SU6668 or AAV-mediated ULK3 RNAi knockdown significantly attenuated BIN1 knockdown-induced hippocampal volume loss, dendritic regression, and spatial memory decline, establishing ULK3 as a functionally relevant autophagy-inducing kinase downstream of BIN1 deficiency in neurons.","method":"AAV-mediated RNAi knockdown, pharmacological inhibition (SU6668), autophagy flux assays, MRI volumetry, Barnes maze behavioral testing, primary hippocampal neuron imaging","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological LOF with defined cellular and behavioral phenotypes, single lab with multiple orthogonal methods","pmids":["39171951"],"is_preprint":false},{"year":2025,"finding":"ULK3 contributes to multiple myeloma cell survival as part of the ULK-ATG13-FIP200 complex. Co-crystallization of ULK3 with novel inhibitors (SG3-014/MA9-060) confirmed their binding mode in the ATP pocket. ULK3 inhibition reduced MM tumor burden in vivo and restored sensitivity to proteasome inhibitors in resistant cells.","method":"Co-crystallization (ULK3 with inhibitors), genetic knockdown/knockout functional assays, in vivo MM tumor models, ex vivo patient sample validation, Co-IP of ULK-ATG13-FIP200 complex","journal":"Research square","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — co-crystal structure plus in vivo functional studies, preprint not yet peer-reviewed","pmids":["40831505"],"is_preprint":true}],"current_model":"ULK3 is a nuclear and cytoplasmic serine/threonine kinase that operates at the intersection of multiple pathways: it phosphorylates ESCRT-III subunits (IST1, CHMP4C) via tandem MIT domains to delay cytokinetic abscission; it positively regulates GLI1/2 transcription factors in the SHH pathway (and is itself suppressed by Sufu binding); it directly binds and activates histone arginine methyltransferases PRMT1/5 to control epigenetic programs in keratinocytes; and it supports autophagosome formation through an MTOR-insensitive mechanism involving interaction with the ATG13-FIP200 complex, with its catalytic activity regulated by an unidentified kinase that phosphorylates two residues in its kinase domain to abolish activity."},"narrative":{"mechanistic_narrative":"ULK3 is a serine/threonine kinase that functions as a multi-pathway signaling node, coupling its catalytic activity to cytokinetic abscission control, Hedgehog-pathway transcription, epigenetic regulation, and autophagy [PMID:26011858, PMID:19878745, PMID:36797248, PMID:27717182]. At the midbody, ULK3 phosphorylates ESCRT-III subunits IST1 and CHMP4C through its tandem MIT domains, an essential signal that sustains the abscission checkpoint and delays cell division in response to lagging chromosomes and midbody tension [PMID:26011858]. In Sonic Hedgehog signaling, ULK3 directly phosphorylates and activates the transcription factors GLI1 and GLI2 and alters GLI1 localization, with its catalytic activity required for this positive regulatory role [PMID:19878745]; this activity is gated by Suppressor of Fused (Sufu), which binds the ULK3 kinase domain, blocks autophosphorylation and GLI phosphorylation, and—when complexed with ULK3—favors the GLI2 repressor form, giving ULK3 both kinase-dependent and kinase-independent functions that are relieved upon SHH-induced complex destabilization [PMID:20643644]. ULK3-driven GLI activation feeds into oncogenic and epigenetic programs, contributing to cancer-associated fibroblast conversion and to transcriptional upregulation of DNMT3A during autophagy [PMID:28877478, PMID:35226587]. In keratinocytes and squamous cell carcinoma, nuclear ULK3 directly binds and regulates the histone arginine methyltransferases PRMT1 and PRMT5, controlling their chromatin association and histone H4 methylation to support proliferation and tumorigenicity [PMID:36797248]. ULK3 also promotes autophagosome formation through an MTOR-insensitive mechanism, acting as part of the ULK–ATG13–FIP200 complex—a role conserved in the Drosophila ortholog ADUK, which requires Atg13 but not Atg1 [PMID:27717182, PMID:39171951, PMID:40831505]. Crystallographic and biochemical analyses define a kinase domain with an active/inactive conformational switch, show that autophosphorylation does not control activity whereas phosphorylation of two kinase-domain residues by an unidentified kinase abolishes it, and establish SU6668 and related compounds as ATP-pocket-binding inhibitors with therapeutic relevance in neuronal autophagy and multiple myeloma models [PMID:30096229, PMID:34190988, PMID:39171951, PMID:40831505].","teleology":[{"year":2009,"claim":"Established ULK3 as a catalytically active kinase with a defined downstream substrate, placing it as a positive regulator within the SHH/GLI transcriptional pathway.","evidence":"In vitro kinase assays, GLI-luciferase reporters, immunofluorescence, and kinase-dead mutant analysis","pmids":["19878745"],"confidence":"Medium","gaps":["GLI phosphorylation sites not mapped","in vivo SHH-pathway relevance not established","endogenous regulation of ULK3 activity unknown"]},{"year":2010,"claim":"Identified Sufu as a direct upstream regulator that gates ULK3 activity, revealing a dual kinase-dependent and kinase-independent role for ULK3 in modulating GLI activator versus repressor balance.","evidence":"Reciprocal Co-IP, in vitro kinase assays, GLI-luciferase reporters, and siRNA knockdown","pmids":["20643644"],"confidence":"Medium","gaps":["structural basis of Sufu-ULK3 interaction not defined","mechanism of SHH-induced complex destabilization unresolved"]},{"year":2015,"claim":"Defined a distinct, non-Hedgehog role for ULK3 as the abscission-checkpoint kinase that phosphorylates ESCRT-III subunits via its MIT domains to time cytokinesis.","evidence":"Crystal structures, in vitro phosphorylation assays, Co-IP/binding, mutagenesis, and lagging-chromosome cell biology","pmids":["26011858"],"confidence":"High","gaps":["how diverse stress signals (nuclear pore defects, tension) feed into ULK3 not detailed","regulation of ULK3 at the midbody unknown"]},{"year":2016,"claim":"Showed the autophagy-inducing function of ULK3 is evolutionarily conserved and operates via an Atg13/FIP200-dependent but Atg1-independent route, distinguishing it from the canonical ULK1/2 autophagy machinery.","evidence":"Co-IP of the Drosophila ortholog ADUK with Atg13/FIP200, genetic loss-of-function, autophagy flux, and lifespan analysis","pmids":["27717182"],"confidence":"Medium","gaps":["direct human ULK3 substrates in autophagy not identified","molecular role within the ATG13-FIP200 complex unclear"]},{"year":2017,"claim":"Connected ULK3 to tumor stroma biology, showing CSL-controlled ULK3 drives GLI2-dependent CAF conversion alongside a separable GLI-independent autophagy function.","evidence":"Co-IP, siRNA knockdown, autophagy assays, CAF functional assays, and tumor co-injection models","pmids":["28877478"],"confidence":"Medium","gaps":["mechanism separating GLI versus autophagy outputs not resolved","in vivo specificity of ULK3 silencing not established"]},{"year":2018,"claim":"Revealed that ULK3 catalytic activity is controlled not by autophosphorylation but by inhibitory phosphorylation of two kinase-domain residues by an unidentified kinase, and that the annotated kinase domain alone is insufficient for activity.","evidence":"In vitro kinase assays, MS phosphosite mapping, site-directed mutagenesis, and inhibitor binding kinetics with SU6668","pmids":["30096229"],"confidence":"Medium","gaps":["the upstream kinase phosphorylating ULK3 is unidentified","physiological trigger for inhibitory phosphorylation unknown","role of the 271-300 region structurally undefined"]},{"year":2021,"claim":"Provided high-resolution structures of the ULK3 kinase domain defining an active/inactive conformational switch and a candidate substrate-recognition mechanism, and linked ULK3-GLI1 activity to epigenetic upregulation of DNMT3A during autophagy.","evidence":"X-ray crystallography with inhibitor co-complexes and fingerprinting; proximity ligation assay, ChIP, RT-qPCR, and siRNA knockdown","pmids":["34190988","35226587"],"confidence":"High","gaps":["full-length ULK3 structure not determined","how the conformational switch is set in cells unknown","direct demonstration that ULK3 phosphorylates GLI1 in the DNMT3A context not shown"]},{"year":2023,"claim":"Established a nuclear, chromatin-associated function for ULK3 as a direct binding partner and regulator of PRMT1/5, linking it to histone H4 arginine methylation and SCC tumorigenicity.","evidence":"Reciprocal Co-IP, chromatin fractionation, histone methylation assays, gene silencing, nuclear imaging, and orthotopic cancer models","pmids":["36797248"],"confidence":"High","gaps":["whether ULK3 kinase activity is required for PRMT regulation not resolved","PRMT substrate specificity changes induced by ULK3 not detailed"]},{"year":2024,"claim":"Demonstrated ULK3 as a functionally relevant, MTOR-insensitive autophagy-inducing kinase whose inhibition rescues neuronal and behavioral deficits caused by BIN1 deficiency.","evidence":"AAV-mediated RNAi, SU6668 pharmacological inhibition, autophagy flux, MRI volumetry, Barnes maze, and primary neuron imaging","pmids":["39171951"],"confidence":"Medium","gaps":["molecular link between BIN1 loss and ULK3 activation unknown","ULK3 autophagy substrates in neurons not identified"]},{"year":2025,"claim":"Positioned ULK3 within the ULK-ATG13-FIP200 complex as a survival dependency in multiple myeloma and validated ATP-pocket inhibitors as therapeutic tools.","evidence":"Co-crystallization with inhibitors, genetic knockdown/knockout, in vivo MM tumor models, ex vivo patient samples, and Co-IP of the complex (preprint)","pmids":["40831505"],"confidence":"Medium","gaps":["preprint not yet peer-reviewed","mechanism by which ULK3 restores proteasome-inhibitor sensitivity unresolved","direct catalytic targets in MM not defined"]},{"year":null,"claim":"The integration of ULK3's multiple roles remains unresolved: how a single kinase is partitioned between midbody ESCRT-III phosphorylation, nuclear GLI/PRMT regulation, and autophagy initiation, and what upstream kinase sets its activity state, is unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["identity of the inhibitory upstream kinase unknown","no unified model of subcellular partitioning across functions","substrate repertoire in autophagy initiation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5]}],"complexes":["ULK-ATG13-FIP200 complex","Sufu-ULK3 complex"],"partners":["IST1","CHMP4C","GLI1","GLI2","SUFU","PRMT1","PRMT5","ATG13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PHR2","full_name":"Serine/threonine-protein kinase ULK3","aliases":["Unc-51-like kinase 3"],"length_aa":472,"mass_kda":53.4,"function":"Serine/threonine protein kinase that acts as a regulator of Sonic hedgehog (SHH) signaling and autophagy. Acts as a negative regulator of SHH signaling in the absence of SHH ligand: interacts with SUFU, thereby inactivating the protein kinase activity and preventing phosphorylation of GLI proteins (GLI1, GLI2 and/or GLI3). Positively regulates SHH signaling in the presence of SHH: dissociates from SUFU, autophosphorylates and mediates phosphorylation of GLI2, activating it and promoting its nuclear translocation. Phosphorylates in vitro GLI2, as well as GLI1 and GLI3, although less efficiently. Also acts as a regulator of autophagy: following cellular senescence, able to induce autophagy","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6PHR2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ULK3","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1090,"dependency_fraction":0.006422018348623854},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000140474","cell_line_id":"CID001301","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"RCBTB2","stoichiometry":10.0},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"MKI67","stoichiometry":0.2},{"gene":"TPR","stoichiometry":0.2},{"gene":"SPTBN1","stoichiometry":0.2},{"gene":"NUP210","stoichiometry":0.2},{"gene":"RCL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001301","total_profiled":1310},"omim":[{"mim_id":"613472","title":"UNC51-LIKE KINASE 3; ULK3","url":"https://www.omim.org/entry/613472"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Acrosome","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ULK3"},"hgnc":{"alias_symbol":["DKFZP434C131","FLJ90566"],"prev_symbol":[]},"alphafold":{"accession":"Q6PHR2","domains":[{"cath_id":"3.30.200.20","chopping":"15-93","consensus_level":"high","plddt":92.4442,"start":15,"end":93},{"cath_id":"1.10.510.10","chopping":"98-271","consensus_level":"high","plddt":95.7491,"start":98,"end":271},{"cath_id":"1.20.58.80","chopping":"280-350","consensus_level":"high","plddt":92.2207,"start":280,"end":350},{"cath_id":"1.20.58.80","chopping":"365-448","consensus_level":"high","plddt":88.5858,"start":365,"end":448}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PHR2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PHR2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PHR2-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ULK3","jax_strain_url":"https://www.jax.org/strain/search?query=ULK3"},"sequence":{"accession":"Q6PHR2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PHR2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PHR2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PHR2"}},"corpus_meta":[{"pmid":"26011858","id":"PMC_26011858","title":"ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26011858","citation_count":83,"is_preprint":false},{"pmid":"19878745","id":"PMC_19878745","title":"Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19878745","citation_count":66,"is_preprint":false},{"pmid":"20643644","id":"PMC_20643644","title":"Dual function of UNC-51-like kinase 3 (Ulk3) in the Sonic hedgehog signaling pathway.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20643644","citation_count":44,"is_preprint":false},{"pmid":"34615546","id":"PMC_34615546","title":"Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34615546","citation_count":43,"is_preprint":false},{"pmid":"28877478","id":"PMC_28877478","title":"The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28877478","citation_count":41,"is_preprint":false},{"pmid":"27717182","id":"PMC_27717182","title":"Atg1-independent induction of autophagy by the Drosophila Ulk3 homolog, ADUK.","date":"2016","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/27717182","citation_count":25,"is_preprint":false},{"pmid":"35226587","id":"PMC_35226587","title":"ULK3-dependent activation of GLI1 promotes DNMT3A expression upon autophagy induction.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35226587","citation_count":20,"is_preprint":false},{"pmid":"36797248","id":"PMC_36797248","title":"The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36797248","citation_count":17,"is_preprint":false},{"pmid":"33289601","id":"PMC_33289601","title":"Promoting roles of long non-coding RNA FAM83H-AS1 in bladder cancer growth, metastasis, and angiogenesis through the c-Myc-mediated ULK3 upregulation.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/33289601","citation_count":14,"is_preprint":false},{"pmid":"39171951","id":"PMC_39171951","title":"BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39171951","citation_count":12,"is_preprint":false},{"pmid":"34190988","id":"PMC_34190988","title":"Conformational plasticity of the ULK3 kinase domain.","date":"2021","source":"The Biochemical 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Disease","date":"2024-12-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.04.24318434","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9116,"output_tokens":3107,"usd":0.036977,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10484,"output_tokens":4055,"usd":0.076897,"stage2_stop_reason":"end_turn"},"total_usd":0.113874,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"ULK3 phosphorylates ESCRT-III subunits (including IST1 and CHMP4C) via tandem MIT domains, delaying cytokinetic abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Structural and biochemical studies revealed an unusually tight interaction between ULK3 and IST1. IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint, and ULK3 and CHMP4C are functionally linked components of the abscission timer.\",\n      \"method\": \"Structural studies, in vitro phosphorylation assays, Co-IP/binding assays, mutagenesis, cell biological assays with lagging chromosome readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural, biochemical reconstitution, mutagenesis, and cellular epistasis all in one rigorous study\",\n      \"pmids\": [\"26011858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ULK3 is an autophosphorylated serine/threonine kinase that phosphorylates GLI1 and GLI2 transcription factors in vitro, enhances their transcriptional activity, and alters subcellular localization of GLI1. Catalytic activity of ULK3 is required for its positive regulatory function in the SHH pathway.\",\n      \"method\": \"In vitro kinase assay, GLI-luciferase reporter assay, immunofluorescence, immunoblotting, kinase-dead mutant analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus reporter assays and localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19878745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ULK3 interacts with Suppressor of Fused (Sufu) through its kinase domain. Sufu blocks ULK3 autophosphorylation and abolishes ULK3-mediated phosphorylation and positive regulation of GLI proteins. SHH signaling destabilizes the Sufu-ULK3 complex and releases ULK3. The Sufu-ULK3 complex co-expressed with GLI2 promotes generation of the GLI2 repressor form, establishing a dual (kinase-dependent and kinase-independent) function for ULK3 in SHH signaling.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, GLI-luciferase reporter assay, siRNA knockdown, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional follow-up, in vitro kinase assay, single lab with multiple methods\",\n      \"pmids\": [\"20643644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Decreased CSL upregulates ULK3 expression in human dermal fibroblasts. ULK3 binds and activates GLI2, thereby contributing to conversion of fibroblasts into cancer-associated fibroblasts (CAFs). ULK3 also independently induces autophagy in this context (unlinked from GLI/CAF activation). ULK3 silencing suppresses the tumor-enhancing properties of CAFs.\",\n      \"method\": \"Co-immunoprecipitation (ULK3-GLI2 binding), siRNA knockdown, autophagy assays, CAF functional assays, tumor co-injection models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for binding, KD with defined CAF/autophagy phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28877478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ULK3-dependent activation of GLI1 contributes to transcriptional upregulation of DNMT3A upon autophagy induction, linking ULK3 kinase activity in the SHH pathway to epigenetic regulation of autophagy-related gene expression. Proximity ligation assay confirmed ULK3-GLI1 interaction in this context.\",\n      \"method\": \"Proximity ligation assay (PLA), chromatin immunoprecipitation (ChIP), RT-qPCR, siRNA knockdown, autophagy induction assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — PLA for interaction, ChIP for transcriptional regulation, siRNA KD, single lab with multiple methods\",\n      \"pmids\": [\"35226587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ULK3 localizes to the nucleus in keratinocytes and SCC cells, where it directly binds and regulates the activity of histone arginine methyltransferases PRMT1 and PRMT5. ULK3 loss compromises PRMT1/5 chromatin association at specific genes and reduces overall methylation of histone H4. ULK3 silencing reduces proliferation, clonogenicity, and tumorigenic potential of SCC cells.\",\n      \"method\": \"Co-IP (ULK3-PRMT1/5 binding), chromatin fractionation, histone methylation assays, gene silencing (siRNA, LNA), nuclear localization imaging, orthotopic cancer models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, chromatin assays, histone methylation readout, functional KD in multiple SCC models, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36797248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Drosophila ULK3 ortholog ADUK induces autophagy independently of Atg1. ADUK interacts with Atg1 complex members Atg13 and FIP200 (200 kDa FAK family kinase-interacting protein), and requires Atg13 but not Atg1 for autophagy induction. Loss of ADUK shortens adult lifespan and reduces the autophagic response to chemical stress.\",\n      \"method\": \"Co-immunoprecipitation (ADUK-Atg13/FIP200), genetic loss-of-function (ADUK mutant flies), autophagy flux assays, lifespan analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic LOF in Drosophila ortholog, single lab with multiple methods\",\n      \"pmids\": [\"27717182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Autophosphorylation of ULK3 has no impact on its kinase activity. Phosphorylation of two specific residues in the ULK3 kinase domain by an unidentified kinase completely abolishes catalytic activity. The small molecule SU6668 binds in the ATP pocket of ULK3 yet inhibits ULK3 in a partially ATP non-competitive manner. The annotated kinase domain alone is insufficient for ULK3 kinase activity; additional amino acids in the 271–300 region are required.\",\n      \"method\": \"In vitro kinase assay, phosphorylation site mapping (mass spectrometry), site-directed mutagenesis, inhibitor binding studies (competitive kinetics)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and inhibitor kinetics, single lab with multiple biochemical methods\",\n      \"pmids\": [\"30096229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"High-resolution crystal structures of the ULK3 kinase domain were determined, revealing unique structural features compared to other ULK kinases. A conformational switch between active and inactive ULK3 conformations was identified, controlled by the properties of attached small-molecule binders. A potential substrate-recognition mechanism of full-length ULK3 was described based on structural analysis.\",\n      \"method\": \"X-ray crystallography of ULK3 kinase domain, inhibitor co-crystallization, inhibitor fingerprinting panel\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structures with multiple inhibitor complexes and conformational analysis, single lab but structurally rigorous\",\n      \"pmids\": [\"34190988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ULK3 expression is MTOR-insensitive and supports autophagosome formation in BIN1-deficient hippocampal neurons. Reducing ULK3 activity with SU6668 or AAV-mediated ULK3 RNAi knockdown significantly attenuated BIN1 knockdown-induced hippocampal volume loss, dendritic regression, and spatial memory decline, establishing ULK3 as a functionally relevant autophagy-inducing kinase downstream of BIN1 deficiency in neurons.\",\n      \"method\": \"AAV-mediated RNAi knockdown, pharmacological inhibition (SU6668), autophagy flux assays, MRI volumetry, Barnes maze behavioral testing, primary hippocampal neuron imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological LOF with defined cellular and behavioral phenotypes, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39171951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ULK3 contributes to multiple myeloma cell survival as part of the ULK-ATG13-FIP200 complex. Co-crystallization of ULK3 with novel inhibitors (SG3-014/MA9-060) confirmed their binding mode in the ATP pocket. ULK3 inhibition reduced MM tumor burden in vivo and restored sensitivity to proteasome inhibitors in resistant cells.\",\n      \"method\": \"Co-crystallization (ULK3 with inhibitors), genetic knockdown/knockout functional assays, in vivo MM tumor models, ex vivo patient sample validation, Co-IP of ULK-ATG13-FIP200 complex\",\n      \"journal\": \"Research square\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-crystal structure plus in vivo functional studies, preprint not yet peer-reviewed\",\n      \"pmids\": [\"40831505\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ULK3 is a nuclear and cytoplasmic serine/threonine kinase that operates at the intersection of multiple pathways: it phosphorylates ESCRT-III subunits (IST1, CHMP4C) via tandem MIT domains to delay cytokinetic abscission; it positively regulates GLI1/2 transcription factors in the SHH pathway (and is itself suppressed by Sufu binding); it directly binds and activates histone arginine methyltransferases PRMT1/5 to control epigenetic programs in keratinocytes; and it supports autophagosome formation through an MTOR-insensitive mechanism involving interaction with the ATG13-FIP200 complex, with its catalytic activity regulated by an unidentified kinase that phosphorylates two residues in its kinase domain to abolish activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ULK3 is a serine/threonine kinase that functions as a multi-pathway signaling node, coupling its catalytic activity to cytokinetic abscission control, Hedgehog-pathway transcription, epigenetic regulation, and autophagy [#0, #1, #5, #6]. At the midbody, ULK3 phosphorylates ESCRT-III subunits IST1 and CHMP4C through its tandem MIT domains, an essential signal that sustains the abscission checkpoint and delays cell division in response to lagging chromosomes and midbody tension [#0]. In Sonic Hedgehog signaling, ULK3 directly phosphorylates and activates the transcription factors GLI1 and GLI2 and alters GLI1 localization, with its catalytic activity required for this positive regulatory role [#1]; this activity is gated by Suppressor of Fused (Sufu), which binds the ULK3 kinase domain, blocks autophosphorylation and GLI phosphorylation, and—when complexed with ULK3—favors the GLI2 repressor form, giving ULK3 both kinase-dependent and kinase-independent functions that are relieved upon SHH-induced complex destabilization [#2]. ULK3-driven GLI activation feeds into oncogenic and epigenetic programs, contributing to cancer-associated fibroblast conversion and to transcriptional upregulation of DNMT3A during autophagy [#3, #4]. In keratinocytes and squamous cell carcinoma, nuclear ULK3 directly binds and regulates the histone arginine methyltransferases PRMT1 and PRMT5, controlling their chromatin association and histone H4 methylation to support proliferation and tumorigenicity [#5]. ULK3 also promotes autophagosome formation through an MTOR-insensitive mechanism, acting as part of the ULK–ATG13–FIP200 complex—a role conserved in the Drosophila ortholog ADUK, which requires Atg13 but not Atg1 [#6, #9, #10]. Crystallographic and biochemical analyses define a kinase domain with an active/inactive conformational switch, show that autophosphorylation does not control activity whereas phosphorylation of two kinase-domain residues by an unidentified kinase abolishes it, and establish SU6668 and related compounds as ATP-pocket-binding inhibitors with therapeutic relevance in neuronal autophagy and multiple myeloma models [#7, #8, #9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established ULK3 as a catalytically active kinase with a defined downstream substrate, placing it as a positive regulator within the SHH/GLI transcriptional pathway.\",\n      \"evidence\": \"In vitro kinase assays, GLI-luciferase reporters, immunofluorescence, and kinase-dead mutant analysis\",\n      \"pmids\": [\"19878745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GLI phosphorylation sites not mapped\", \"in vivo SHH-pathway relevance not established\", \"endogenous regulation of ULK3 activity unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified Sufu as a direct upstream regulator that gates ULK3 activity, revealing a dual kinase-dependent and kinase-independent role for ULK3 in modulating GLI activator versus repressor balance.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro kinase assays, GLI-luciferase reporters, and siRNA knockdown\",\n      \"pmids\": [\"20643644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of Sufu-ULK3 interaction not defined\", \"mechanism of SHH-induced complex destabilization unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a distinct, non-Hedgehog role for ULK3 as the abscission-checkpoint kinase that phosphorylates ESCRT-III subunits via its MIT domains to time cytokinesis.\",\n      \"evidence\": \"Crystal structures, in vitro phosphorylation assays, Co-IP/binding, mutagenesis, and lagging-chromosome cell biology\",\n      \"pmids\": [\"26011858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how diverse stress signals (nuclear pore defects, tension) feed into ULK3 not detailed\", \"regulation of ULK3 at the midbody unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the autophagy-inducing function of ULK3 is evolutionarily conserved and operates via an Atg13/FIP200-dependent but Atg1-independent route, distinguishing it from the canonical ULK1/2 autophagy machinery.\",\n      \"evidence\": \"Co-IP of the Drosophila ortholog ADUK with Atg13/FIP200, genetic loss-of-function, autophagy flux, and lifespan analysis\",\n      \"pmids\": [\"27717182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct human ULK3 substrates in autophagy not identified\", \"molecular role within the ATG13-FIP200 complex unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected ULK3 to tumor stroma biology, showing CSL-controlled ULK3 drives GLI2-dependent CAF conversion alongside a separable GLI-independent autophagy function.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, autophagy assays, CAF functional assays, and tumor co-injection models\",\n      \"pmids\": [\"28877478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism separating GLI versus autophagy outputs not resolved\", \"in vivo specificity of ULK3 silencing not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed that ULK3 catalytic activity is controlled not by autophosphorylation but by inhibitory phosphorylation of two kinase-domain residues by an unidentified kinase, and that the annotated kinase domain alone is insufficient for activity.\",\n      \"evidence\": \"In vitro kinase assays, MS phosphosite mapping, site-directed mutagenesis, and inhibitor binding kinetics with SU6668\",\n      \"pmids\": [\"30096229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"the upstream kinase phosphorylating ULK3 is unidentified\", \"physiological trigger for inhibitory phosphorylation unknown\", \"role of the 271-300 region structurally undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided high-resolution structures of the ULK3 kinase domain defining an active/inactive conformational switch and a candidate substrate-recognition mechanism, and linked ULK3-GLI1 activity to epigenetic upregulation of DNMT3A during autophagy.\",\n      \"evidence\": \"X-ray crystallography with inhibitor co-complexes and fingerprinting; proximity ligation assay, ChIP, RT-qPCR, and siRNA knockdown\",\n      \"pmids\": [\"34190988\", \"35226587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"full-length ULK3 structure not determined\", \"how the conformational switch is set in cells unknown\", \"direct demonstration that ULK3 phosphorylates GLI1 in the DNMT3A context not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a nuclear, chromatin-associated function for ULK3 as a direct binding partner and regulator of PRMT1/5, linking it to histone H4 arginine methylation and SCC tumorigenicity.\",\n      \"evidence\": \"Reciprocal Co-IP, chromatin fractionation, histone methylation assays, gene silencing, nuclear imaging, and orthotopic cancer models\",\n      \"pmids\": [\"36797248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether ULK3 kinase activity is required for PRMT regulation not resolved\", \"PRMT substrate specificity changes induced by ULK3 not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated ULK3 as a functionally relevant, MTOR-insensitive autophagy-inducing kinase whose inhibition rescues neuronal and behavioral deficits caused by BIN1 deficiency.\",\n      \"evidence\": \"AAV-mediated RNAi, SU6668 pharmacological inhibition, autophagy flux, MRI volumetry, Barnes maze, and primary neuron imaging\",\n      \"pmids\": [\"39171951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular link between BIN1 loss and ULK3 activation unknown\", \"ULK3 autophagy substrates in neurons not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned ULK3 within the ULK-ATG13-FIP200 complex as a survival dependency in multiple myeloma and validated ATP-pocket inhibitors as therapeutic tools.\",\n      \"evidence\": \"Co-crystallization with inhibitors, genetic knockdown/knockout, in vivo MM tumor models, ex vivo patient samples, and Co-IP of the complex (preprint)\",\n      \"pmids\": [\"40831505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"preprint not yet peer-reviewed\", \"mechanism by which ULK3 restores proteasome-inhibitor sensitivity unresolved\", \"direct catalytic targets in MM not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The integration of ULK3's multiple roles remains unresolved: how a single kinase is partitioned between midbody ESCRT-III phosphorylation, nuclear GLI/PRMT regulation, and autophagy initiation, and what upstream kinase sets its activity state, is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"identity of the inhibitory upstream kinase unknown\", \"no unified model of subcellular partitioning across functions\", \"substrate repertoire in autophagy initiation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"ULK-ATG13-FIP200 complex\", \"Sufu-ULK3 complex\"],\n    \"partners\": [\"IST1\", \"CHMP4C\", \"GLI1\", \"GLI2\", \"SUFU\", \"PRMT1\", \"PRMT5\", \"ATG13\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}